Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties

Research output: Contribution to journalArticle

Authors

  • David G Smith
  • Roberta Martinelli
  • Istvan Szatmari
  • Peter Brazda
  • Mary A Allen
  • Wenqing Xu
  • Xiang Wang
  • László Nagy
  • Robin D Dowell
  • Graham A W Rook
  • Laura Rosa Brunet
  • Christopher A Lowry

Colleges, School and Institutes

External organisations

  • Department of Pathology, Anatomy, and Cellular Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA. david.smith3@jefferson.edu.
  • Merck Research Laboratories, MSD, Kenilworth, NJ, USA.
  • School of Bioscience, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
  • Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Egyetem tér, 1, Debrecen, 4032, Hungary.
  • BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, 80303, USA.
  • Department of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, CO, 80309, USA.
  • Department of Medicine, Johns Hopkins University, Johns Hopkins All Children's Hospital, Saint Petersburg, FL, 33701, USA.
  • University College London
  • inVIVO Planetary Health, of the Worldwide Universities Network (WUN), West New York, NJ, 07093, USA. christopher.lowry@colorado.edu.

Abstract

RATIONALE: Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation in a murine model of allergic asthma. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory effects of M. vaccae are not known.

OBJECTIVES: Our objective was to identify and characterize novel anti-inflammatory molecules from M. vaccae NCTC 11659.

METHODS: We have purified and identified a unique anti-inflammatory triglyceride, 1,2,3-tri [Z-10-hexadecenoyl] glycerol, from M. vaccae and evaluated its effects in freshly isolated murine peritoneal macrophages.

RESULTS: The free fatty acid form of 1,2,3-tri [Z-10-hexadecenoyl] glycerol, 10(Z)-hexadecenoic acid, decreased lipopolysaccharide-stimulated secretion of the proinflammatory cytokine IL-6 ex vivo. Meanwhile, next-generation RNA sequencing revealed that pretreatment with 10(Z)-hexadecenoic acid upregulated genes associated with peroxisome proliferator-activated receptor alpha (PPARα) signaling in lipopolysaccharide-stimulated macrophages, in association with a broad transcriptional repression of inflammatory markers. We confirmed using luciferase-based transfection assays that 10(Z)-hexadecenoic acid activated PPARα signaling, but not PPARγ, PPARδ, or retinoic acid receptor (RAR) α signaling. The effects of 10(Z)-hexadecenoic acid on lipopolysaccharide-stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice.

CONCLUSION: Future studies should evaluate the effects of 10(Z)-hexadecenoic acid on stress-induced exaggeration of peripheral inflammatory signaling, central neuroinflammatory signaling, and anxiety- and fear-related defensive behavioral responses.

Details

Original languageEnglish
Pages (from-to)1653-1670
Number of pages18
JournalPsychopharmacology
Volume236
Issue number5
Early online date22 May 2019
Publication statusE-pub ahead of print - 22 May 2019

Keywords

  • 10(Z)-hexadecenoic acid, Bacteria, Inflammation, Interleukin 6, Lipid, Macrophage, Mycobacteria, PPAR, RNA-seq, vaccae

ASJC Scopus subject areas